MS is an autoimmune disease affecting over 350,000 patients in the US in which the immune system attacks the myelin sheaths that insulate CNS axons, with secondary axonal damage contributing to long-term disability. The disease is associated with the major histocompatibility complex (MHC) class II molecule HLA- DR2 (DRA, DRB1*1501 ) that binds peptide antigens and presents them to T cells, initiating an immune response. Blockade of the HLA-DR2 binding site to prevent antigen binding and T cell activation is a strategy designed to disrupt the autoimmune process, leading to a decrease in disease activity and symptoms. This proposal is directed toward the demonstration of biological feasibility of this strategy. Prototypical small molecules peptide mimetics (PV-72, PV-245) developed by Provid Pharmaceuticals bind with low nanomolar affinity to DR2, are stabilized against cathepsin protease degradation, and have high selectivity for HLA-DR2. In this phase I proposal, these compounds will be tested for inhibition of T-cell activation in transgenic mice expressing human DR2. They will also be evaluated for both prevention and treatment of experimental autoimmune encephalitis (EAE) in the DR2 transgenic mice. The success of this phase I proposal will be determined in the demonstration of biological efficacy for the inhibition T-cell responses due to the blockade of the DR2 binding site by the small molecule peptide mimetics developed for this purpose. Further lead optimization is to follow this proof of concept study, and should lead to a clinical candidate for drug development for the treatment of the disease process in multiple sclerosis.